The present invention relates devices and methods for transporting fluids across biological barriers, for example, for purposes of administering drugs, sampling the tissue for the presence and concentration of substances, or for any other medical or research purpose. More specifically, the present invention relates to microneedle devices with features and corresponding methods for enhancing skin penetration, as well as to devices and methods which employ a combination of shallow penetration by hollow microneedles followed by jet injection via the microneedles.
Research and development of microneedle arrays has advanced in recent years as part of a system for drug delivery or biological sampling. In these applications, the microneedle approach shows clear advantages over competing methods of transferring fluids through skin or other barriers. In contrast to hypodermic needles, microneedles are relatively painless and can be self administered or administered by nonprofessionals. In addition, they overcome the molecular size limitations characteristic of conventional transdermal patches. Examples of such work may be found in PCT Publications Nos. WO 01/66065 and WO 02/17985, both co-assigned with the present application. These publications are hereby incorporated by reference as if set out in their entirety herein. Other relevant publications include WO 99/64580 and WO 00/74763 to Georgia Tech Research Corp., as well as in the following scientific publications: “Micro machined needles for the transdermal delivery of drugs”, S. H. S. Henry et al. (MEMS 98, Heildelberg, Germany, January 1998); “Three dimensional hollow micro needle and microtube arrays”, D. V. McAllister et al. (Transducer 99, Sendai, Japan, June 1999); “An array of hollow micro-capillaries for the controlled injection of genetic materials into animal/plant cells”, K. Chun et al. (MEMS 99, Orlando, Fla., January 1999); and “Injection of DNA into plant and animal tissues with micromechanical piercing structures”, W. Trimmer et al. (IEEE workshop on MEMS, Amsterdam, January 1995). The aforementioned PCT applications disclose the use of hollow microneedles to provide a flow path for fluid flow through the skin barrier.
While hollow microneedles are potentially an effective structure for transferring fluids across a biological barrier, the devices proposed to date suffer from a number of drawbacks that limit or prevent their functionality. Current microneedle array devices do not reliably penetrate the biological barrier, preventing or diminishing cross-barrier transfer of fluids. In the case of administering drugs through human skin, the transfer is ineffective if the microneedle does not pierce at least the stratum corneum layer. In many cases, the skin surface is elastic enough to stretch around each microneedle without being pierced.
Various approaches have been proposed to ensure sufficient penetration into the skin. One approach has been to use very long and sharp microneedles. While achieving greater penetration, the microneedles produced by this method are more fragile and more difficult to manufacture. A different approach is suggested by the aforementioned WO 00/74763 to Georgia Tech which proposes various complicated mechanical devices to stretch the skin. U.S. Pat. No. 6,440,096 to Lastovish et al. discloses an arrangement for stretching the skin by use of a suction cup constructed around the device. Yet another approach is based on diminishing the elasticity of the skin by freezing or otherwise changing the mechanical properties of the skin prior to penetration. All of these approaches clearly suffer from complexity of use and/or production.
In the field of surgical tools for use during surgical procedures, it is known to use ultrasonic vibrations to enhance the effect of a cutting or separating tool as in U.S. Pat. No. 4,832,683 to Idemoto et al. Ultrasonic vibrations have been a feature of surgical devices intended for use by skilled personnel, but have not been previously applied to enhance penetration of microneedles into a biological barrier.
It is also known to employ a needleless injector as an alternative to a hollow needle for injection of fluid into the body. These injectors use a fine stream or “jet” of pressurized liquid to penetrate the skin. Early designs used high pressure throughout the injection, to punch a hole through the tough stratum corneum and epidermis. However, the bulk of the injection could then be infused along the initial track under much lower pressure. U.S. Pat. No. 2,704,542 to Scherer and U.S. Pat. No. 3,908,651 to Fudge disclose examples of this design. Ultimately, the engineering demands of changing the pressure during the injection and resulting complexity, the cost, and the pain associated, have limited the use of such devices.
In most cases, modern high-pressure needleless jet injectors are driven by pressure from a pressurized gas cylinder as exemplified by U.S. Pat. Nos. 6,063,053 and 6,264,629. 5,499,972 teaches a jet injection device powered by a powerful cocked spring. Of most relevance to the present invention are U.S. Pat. Nos. 6,102,896 and 6,224,567 which teach a jet injection device where the pressure is generated manually by pressing on a cap. When sufficient force is applied, a mechanical obstruction is overcome to actuate the pressure jet.
While jet injectors offer advantages of somewhat reduced pain and potentially improved hygiene compared to conventional needle injections, they still suffer from many drawbacks. Most notably, since there is no sealed conduit between the drug supply and the target tissue, significant wastage of the drug occurs. This also results in lack of precision in the administered dosage of a drug. Furthermore, penetration through the strong tissue of the upper layers of the skin requires high activation pressures which typically require complex and expensive systems. The use of purely manual pressure for activation may raise questions of reliability.
There is therefore a need for devices and methods which would enhance the penetration of a biological barrier, particularly the stratum corneum, by microneedles. There is also a need for a device and method which would achieve relatively painless shallow penetration by use of hollow microneedles followed by jet injection via the microneedles. Since 70% of the resistance of the skin is attributed to the stratum corneum layer, mechanical penetration of this layer prior to use of jet injection allows use of lower energy jet injection streams and correspondingly simpler actuation mechanisms.